Phenomenon of polymorphism in pharmacy (in nature)

Transkript

1 DEPARTMENT OF SOLID STATE CHEMISTRY Phenomenon of polymorphism in pharmacy (in nature) Bohumil Kratochvíl Chemie a fyzika pevných léčiv

2 Polymorphism Polymorphism is the ability of existence multiple forms from one entity (name from the Greek roots: poly, πολύ = many and morphe, μορφή = form, shape) Polymorphism (genetics) - is the branching of the genetic tree, caused by two or more gene forms occurring at one DNA position or in one DNA region, each with appreciable frequency in the population Polymorphism (molecular biology) - variability in cell cultures Polymorphism (programming) - property programming language Polymorphism (psychology) - variability of moods Polymorphism (crystallography, pharmacy, mineralogy, material science) - the ability of compound (substance, mineral) to crystallize in different crystal modifications or polymorphs 2

3 Historical background Jean Baptiste Louis Romé de l Isle ( ) salina sodium chloride NaCl cube NaCl octahedron (crystallisation in the presence of urea) Rock-salt (NaCl) may, depending on the crystallization conditions, crystallizes in two crystal shapes today definition of Crystal morphology (crystal habit) 3

4 Crystal morphology (crystal habit) vs. polymorphism (allotropism) Crystal morphology of diamonds Polymorphism of and 1,3-bis(m-nitrophenyl) urea Crystal morphology is not connected with the crystal structure change Polymorphism is connected with the crystal structure change and mostly with the change of crystal habit 4

5 Polymorfismus vs. Krystalová morfologie Krystalová morfologie (krystalový design) určitá substance může z různých rozpouštědel vykrystalizovat v různých tvarech, aniž se změní její krystalová struktura (nejedná se o polymorfismus!) Různé krystalové tvary acetylsalicylové kyseliny krystalované z různých rozpouštědel (převzato z Byrn R. S., Pfeiffer R. R., Stowell G.J.: Solid-State Chemistry of Drugs, 2nd ed. SSCI, Inc. West Lafayette, Indiana 1999).

6 Examples of polymorphism Compound Polymorphs Application zinc sulfide sphalerite, wurtzite semiconductors titanium oxide rutile, anatase, brookite pigment zirconium oxide monoclinic, tetragonal, cubic ceramics aluminium oxide -Al 2 O 3, -Al 2 O 3, g-al 2 O 3 ceramics titanium chloride -TiCl 3, -TiCl 3, g-ticl 3, d-ticl 3 catalyst tungsten trioxide ε-, δ-, γ-, β-, α-wo 3 pigment paracetamol I, II, III pharmaceutical cabergoline I, II, VII, L pharmaceutical terguride A, B, C, D, E, F pharmaceutical ROY 10 polymorphs organics saccharose no polymorphism! sugar We do not know exactly why the compounds form polymorphs? 6

7 Vlastnosti polymorfů Nejdůležitější rozdíly mezi polymorfy jsou v rozpouštěcí rychlosti

8 Categories of polymorphism Packing polymorphism - molecule is rigid, polymorphs differ only its repetition in the crystal polymorph I polymorph III sulfapyridine polymorph II polymorph IV 8

9 Categories of polymorphism Conformational polymorphism - molecule is flexible and forms conformers which crystallize in different polymorphs two rotamers of glutamic acid (ionized) - polymorph - polymorph 9

10 Conformational polymorphs of simvastatin HO O O O H O Simvastatin a cholesterol lowering pharmaceutics room-temperature polymorph I 261 K low-temperature polymorph II Hušák M., Kratochvíl B., Jegorov A.: Acta Crystallogr. A64, C211 (2008). 10

11 Polymorphic system of aspirine Theoretically interesting only dimorphic acetylsalicylic acid polymorph I (formulated in Aspirin) polymorph II Wishweshwar P. et al.:jacs 127, (2005).

12 Polymorfismus ve farmacii pouze monitorujeme, zatím ho nedovedeme fundamentálně vysvětlit proč jsou některé farmaceutické molekuly polymorfní a některé monomorfní? Polymorfismus je pro farmaceutické firmy omezující fenomén Polymorfismus si farmaceutické firmy nemohou dovolit ignorovat Polymorfismus je sledovaným fenoménem ze strany regulačních (registračních) institucí

13 Základní otázky polymorfismu řešené ve farmaceutickém výzkumu, vývoji, výrobě a kontrole Jaká je frekvence výskytu polymorfů u určité, farmaceuticky zajímavé molekuly? Lze polymorfii teoreticky předpovědět? Jak připravit zvolený polymorf dostatečně robustní, kontrolovanou a reprodukovatelnou technologií? Jaké jsou podobnosti a rozdíly ve vlastnostech jednotlivých polymorfů od určité molekuly? Neohrozí záměna polymorfu zdraví pacienta? Jaké, dostatečně citlivé a validované analytické techniky se hodí k identifikaci, rozlišení a stanovení polymorfů?

14 Frequency of polymorphisms Each molecule is potentially polymorphic - dimorphism ( 91 %), trimorphism (8 %), tetramorphism (0.9 %), pentamorphism (< 0.1%).... (as followed from inspection of the Cambridge Structural Database) Walter McCrone, 1963 "every compound has different polymorphic forms, and that, in general, the number of forms known for a given compound is proportional to the time and money spent in research on that compound." Yu L.: Acc.Chem.Res. 43(9), 1257 (2010). Decamorphism of ROY compound (intermediate of olanzapine) 14

15 Saccharose has no polymorphs crystalline saccharose glass saccharose crystal structure of saccharose 15

16 Polymorfní systém a transformace polymorfů V polymorfním systému existuje termodynamická hierarchie stability polymorfů: stabilní polymorf a metastabilní (nestabilní) polymorfy Stabilní polymorf je charakterizován: nejnižší Gibbsovou energií nejnižší rozpustností v libovolném rozpouštědle nejnižší rozpouštěcí rychlostí nejnižší biodostupností nejnižší reaktivitou Pro formulaci se dají použít i nestabilní, ale stálé polymorfy

17 Stability of polymorphs The thermodynamic hierarchy of the stability in the polymorphic system : only one stable polymorph and other metastable (unstable) polymorphs G H TS The stable polymorph is characterized by : lowest Gibbs energy (for free selected values of p and T) J. W. Gibbs lowest dissolution rate in any solvent lowest reactivity Termodynamic stability and kinetic stability 11

18 S / J.K -1.mol V / m 3.mol -1 Transformation of polymorphs 1st order phase transformation (P. Ehrenfest, 1933) Gibbs energy dependence on T and p is continuous, jumping changes only first derivative of G G S T p dg SdT Vdp G p T V Monoclinic Monoclinic ZrO 2 Monoclinic Monoclinic ZrO S = 4,6 J.K -1.mol -1 V = -1, m 3.mol Tetragonal T / K Tetragonal Tetragonal p / kbar 18

19 G m [kj/mol] Enantiotropic polymorph transformation liquid -400 II(s) I(s) A C -600 B T tr (I/II) T F (I/liquid) T F (II/liquid) T [K] 19

20 G m [kj/mol] Monotropic polymorph transformation 0 liquid -200 II(s) -400 I(s) B -600 C A T F (II/liquid) T F (I/liquid) T tr (I/II) T [K] 20

21 Enantiotropy vs. Monotropy Pharmaceutical substance nicergoline Polymorph I crystallizes from polar solvents (MeOH, EtOH) Polymorph II crystallizes from unpolar solvents (toluen) Inorganic polymorph systems are mostly enantiotropic and visualized by phase diagrams Organic (pharmaceutical) polymorph systems are mostly monotropic (solvent-mediated transformation) 21

22 Nekontrolovatelné polymorfní přechody - neštěstí farmacie (hysterezní, špatně definované, často probíhají přes kapalnou fázi) Kde může ve farmaceutické výrobě dojít k polymorfní přeměně: při finální krystalizaci aktivní substance ( disappearing polymorph ) při dlouhodobém stání produktu v matečném roztoku při sušení produktu při mikronizaci (homogenizaci) při vhlké granulaci při tabletaci v lékové formě (tabletě - vliv excipientů)

23 Predikce polymorfismu - není zatím obecně možná predikce krystalové struktury (výpočet mřížkové energie při 0K identifikace správného řešení? chyby výpočtu jsou srovnatelné s energetickými rozdíly mezi polymorfy! ) predikce krystalizačních podmínek Teoretický výpočet mřížkových energií možných struktur molekulární simulace Cerius/Materials Studio - Polymorph Predictor předpověd existence paracetamolu formy III předpověď existence aspirinu formy II Predikce polymorfie se při patentových sporech neuznává (Lee, 2002)!

24 Polymorphism of pharmaceutical substances and excipients Dostinex, Pfizer drug for regulating of women milk production (prescription information leaflet, PIL: polymorphs are not mentioned) Contents of one tablet: cabergolinum 0,5 mg, excipients are: lactose (filler and binder) and leucine (taste correction) Active substance: cabergoline 4 polymorphs (I, II, VII, L) Excipient: lactose 2 polymorphs (, ) 8 polymorphic combinations are possible for formulation of DOSTINEX??? 24

25 Polymorphs have different properties Polymorphs of one chemical entity can have different properties such as melting point, chemical reactivity, dissolution rate, optical and electrical properties, vapor pressure, and density. These properties can a direct impact on the process-ability of drug substances and the quality/performance of drug products, such as stability and bioavailability. Polymorph mixture of chloramphenicol Polymorph A: stable but non active Polymorph B: unstable but active Polymorphs A and B differ 10x in their dissolution rates Polymorph A does not reach the active concentration in the blood Haleblian J. et al.: J.Pharm.Sci.58, 911 (1969). Pharmacokinetic profiles of chloramphenicol B/A 25

26 Uncontrollable polymorph transformation in the pharma manufacture during final crystallization of the substance during prolonged standing of the product in the mother liquor during homogenization (milling/micronization operations) during wet granulation during tabletation during exposure of excipients in dosage form Monitoring and documentation of polymorphic purity of drugs require control authorities (EMA, FDA, SUKL...) directive of the International Conference on Harmonization (ICH) Guideline Q6A 26

27 Preventing unwanted polymorph transformation control of crystallization parameters temperature evaporation rate of the solvent cooling rate of the solution water content in the solvent the presence of impurities in the solution standing time of the product in the mother liquor the degree of supersaturation of the solution the choice of solvent and its polarity ph of the solution concentration and temperature gradients in the solution mechanical, sound and other shocks in solutions stirring speed of the solution seed crystallization??? 27

28 Unwanted polymorphic transition in drug production ( diappearing polymorph ) Ritonavir, HIV-protease inhibitor (Norvir, Abbot Laboratories, now AbbVie) Polymorph I Polymorph II Making Crystals by Design: Braga D. and Grepioni F. (Eds). Wiley-VCH Weinheim In 1996 launched unstable polymorph I (as identified later) In 1998 discovered second polymorph II (stable) - bad dissolution profile In unsuccessful attempt to master this polymorphic system In 1999 reformulation to new dosage form (soft gelatin capsule + solution) In 2000 tablet form of ritonavir 20

29 Choice of polymorph for the formulation For the formulation can be used also termodynamic unstable, but kinetic stable polymorphs bypassing the original patent protection atorvastatin calcium about 70 phases in patents pharmaceutical Sortis (Pfizer), original - expiration 36 months (form I, atorvastatin calcium. 3H2O) Triglyx (Teva), generics - expiration 24 months (unstable form) Torvacard (Zentiva), generics - expiration 18 months (other unstable form) original generics generics Stable polymorph: worse dissolution rate, long expiration, robust technology Unstable polymorph: better dissolution rate, shorter expiration, problems with robust technology and kinetic stability 29

30 Polymorph screening highthroughput crystallization studies Combinatorial crystallization in the pharmaceutical discovery process - several hundred or thousands crystallization experiments using 20 solvents and their mixtures. Detection of polymorphs in situ by Raman spectroscopy or X-ray powder diffraction Morissette S.L. et al. Advanced Drug Delivery Reviews 56, 275 (2004). 30

31 Polymorph analytics substance dosage form All techniques analyzing crystal or amorphous structures: X-ray diffraction (XRSCD, XRPD), solid state NMR, spectroscopy (Raman, IR, terahertz), thermal methods (TGA, microdsc, hyperdsc), calorimetry (SC, TSC, IMC), microscopy (polarizing optical microscopy, thermomicroscopy, TEM, SEM), dynamic vapor sorption (DVS) Regulatory authorities approve up to 5 % admixture of the second polymorph in substance (Drug Master File), if it does not affect the bioavailability of the drug. The main purpose of the exact analytics of polymorphs is a patent protection!!! 31

32 Pure polymorph or mixture in XRPD Pure phase or mixture? Pure phase : after indexing all peaks! Miller indices Calculating of lattice parameters : a,b,c [Å];,,g [ o ]: l = 2d sin q (Bragg s law) h 2 k 2 l 2 2hk 1/d 2 = [ sin sin sin g (cos cos cos g ) a b c ab 2kl 2lh (cos cos g cos ) (cos g cos cos )]/ bc ca (1 cos cos cos g 2cos cos cos g ) 32

33 Identification of polymorphs by XRPD To identify the new polymorph is not required the indexation of XRPD in the pharmaceutical documentation X-ray diffraction patterns of praezosin hydrochloride - the reproducibility of production batches X-ray diffraction patterns of cabergoline polymorphs 33

34 Quantitative analysis of polymorph by XRPD Current detection limit of X-ray powder diffraction analysis in pharmaceutical polymorph mixtures is 0,1 1 % Detection limit of clopidogrel polymorph mixture Brusová H. in: Moderní přístupy k farmaceutické analýze. VFU Brno,

35 Experimental and calculated XRPD data The comparison of exp. and calc. X-ray powder diffraction data The crystal structure of agomelatin, polymorph I 35

36 XRPD of dosage forms Reverse Engineering (pharmaceutical deformulation) methods that are used in decoding, re-produce and re-design an existing product (both generic and original companies) Electron microscopy of substance, exipients and tablet Identification of clopidogrel polymorph I in the tablet Brusová H. in: Moderní přístupy k farmaceutické analýze. VFU Brno,

37 Patent strategy of original pharma companies Patent disputes between the original and generic companies. Patent exclusivity : ( ) years For generics company it is better to develope and patented its own polymorph and to use it for own formulation 37

38 Polymorph prediction Prediction of alaptide crystal structuresoftware Materials Studio (Accelrys) Patent disputes take into account experiment only, not prediction Total energy, field COMPA SS (kcal/m ol) Dens ity (g/c m3) Space group a(å) b(å) c(å) β( ) 15,97 1,39 P ,0826 6,2411 6, ,70 1,37 P21 6,2487 6, , ,65 16,76 1,37 P ,0104 8,7500 6, ,97 1,38 P21 6,1610 7, , ,163 17,04 1,38 P ,1900 6,1698 7, red - prediction, green - experiment Experim ent 1,47 P ,1417 (3) 6,1463 (6) 7,2222 (4) 90 Calculation Jan Rohlíček and Michal Hušák 38

39 Phase transformation of trans-d-terguride E: terguride. EtOH A: terguride. 2/3 H 2 O M: terguride. MeOH T> 40 o C water suspension 1 hour in air or 3 days at 75% RH B: terguride. H 2 O 6 hrs, 70 o C water suspension several months at 75% RH water suspension C: terguride anhydrous D: terguride. H 2 O F: terguride. 2/3 H 2 O Example of the ideal described polymorphic and solvate system 31

40 Jak mít polymorfní přechody (alespoň částečně) pod kontrolou? screening počtu polymorfů AstraZeneca Krystalizační automat několik set až tisíc krystalizací při použití až 20 rozpouštědel a jejich směsí screening polymorfních přechodů Skanovací transitiometrie: Spojení kalorimetrie a dilatometrie. Kontinuálně se mění tlak a/nebo teplota a měří se objemové, entalpické a tlakové změny indikující fázové přechody. Randzio S.L.: Thermochim. Acta 375, 107 (2000).

41 Jak mít polymorfní přechody (alespoň částečně) pod kontrolou? výběr nejstabilnějšího polymorfu nebo nejstabilnějšího hydrátu (solvátu) polymorfy: stabilní (hůře rozpustné, dlouhá expirace, robustní technologie) metastabilní (dobře rozpustné, kratší expirace, obtížná robustní technologie) nestabilní amorfní a semikrystalické fáze (dobře rozpustné, horší anal. stanovení) (eventualita u generických výrobců) výběr soli (kokrystalu) místo báze tergurid báze krystaluje v 7 formách tergurid hydrogen maleát (sůl) krystaluje v 1 formě jako monohydrát (Mysalfon, dříve vyráběla Teva) acetaminofen (paracetamol) 3 formy kokrystal acetaminofen-piperazin (1:1) 1 forma přísná technologická kázeň (GMP) trans-d-tergurid sterilní filtrace

42 Conclusions Substance polymorphism is widespread phenomenon in pharmacy, which we can describe, but we can not predict and explain its fundamentals Polymorphism is the property of the solid crystalline phase For pharmaceutical companies polymorphism is both unwelcome and welcome phenomenon (original vs. generic companies ) Pharmaceutical companies must carefully monitor a polymorphism purity of their substances Polymorphs of one substance may differ considerably in their dissolution profiles Polymorph impurities are ideal control parameters for regulating authorities Number of analytical methods are available to monitor polymorphism purity in pharmacy, the most commonly used are : XRPD, DSC and FT-IR 42